The incidence of urinary bladder cancer is increasing in most Western countries. Smoking and exposure to chemical carcinogens are regarded as the most important etiological factors. One fourth of bladder carcinomas are muscle invasive at diagnosis, but accounts for about 80% of disease related deaths. Surgical treatment of muscle invasive bladder cancer consists of cystectomy and removal of regional lymph nodes, although the extent of lymph node dissection is disputable. Traditionally in the Nordic countries, the pelvic node dissection has been limited to the obturator fossa bilaterally. Adjuvant and neoadjuvant modalities have been explored for improvement of survival in invasive bladder cancer. Recently, some prospectively randomized studies and combination analyses have been presented, suggesting a limited benefit in survival using different neoadjuvant chemotherapy regimes. Thus, there is a need for additional treatment modalities.
The immune system often appears informed about tumours, as shown by an accumulation of immune cells at tumour sites, which correlates with improved prognosis. Immuno-competent cells respond to “danger” signals, which can be provided of growing tumours as a consequence of the genotoxic stress of cell transformation and disruption of the surrounding microenvironment. Under ideal conditions, these signals will induce inflammation, activate innate effector cells with antitumour activity, and stimulate professional antigen-presenting cells (APCs), particularly dendritic cells (DCs), to engulf tumour-derived antigens and migrate to draining lymph nodes to trigger an adaptive response by T and B lymphocytes. Thus, the immune system is capable of recognizing and eliminating tumour cells but unfortunately tumours often interfere with the development and function of immune responses. However, recent advances in cellular and molecular immunology suggest strategies, which may prevent antitumour responses. Briefly, the presence of a tumour indicates that the developing cancer was able to avoid detection or to escape or to overwhelm the immune response. Progressing tumours often exhibit strategies that promote evasion from immune recognition. Examples are physical exclusion of immune cells from tumour sites, poor immunogenicity due to reduced expression of major histocompatibility complex (MHC) or costimulatory proteins, and disruption of natural killer (NK) and natural killer T (NKT) cell recognition. Further, some tumours prevent triggering of an inflammatory response by secreting proteins such as interleukin 10 (IL-10) or vascular endothelial growth factor (VEGF) that interfere with DC activation and differentiation, or by blocking the production of proinflammatory molecules by increasing expression of the STAT3 protein. Even if a response is induced, tumour cells may escape elimination by losing targeted antigens, rendering tumour-reactive T cells anergic, inducing regulatory T cells, or specifically deleting responding T cells. The tumour that finally develops reflects selection of poorly immunogenic and/or immune-resistant malignant cells.
In the adjuvant setting, tumour immunotherapy offers an appealing alternative to traditional cytostatics. One strategy has been to expand and activate NK cells in vitro with out specific antigen by culture with IL-2 followed by infusion of large numbers of these NK cells back into patients alone or with high doses of IL-2. This approach, or administration of high doses of IL-2 to expand and activate NK cells entirely in vivo, has yielded antitumour activity and remission in a subset of patients (Rosenberg S A et al., J Natl Cancer Inst 85, 622, 1993). However, life-threatening toxicity often develops, largely due to the release of tumour necrosis factor (TNF) from activated NK cells.
Other attempts to stimulate the innate specific T cell immunity have been done by different types of vaccines. Promising results from animal studies entailed a study in which autologous tumour cells and an adjuvant immunomodulating agent, bacillus Calmette-Guérin (BCG) was given in combination several times to 98 patients with colorectal cancer in a prospectively randomized study. No statistically significant differences were detected in survival but maybe a small decrease in recurrence rate in stage 11 colon cancer patients.
Thus, it is obvious that there is still a need for an effective and at the same time safe treatment of bladder cancer and metastases of bladder cancer.